Analysis of cancer in humans and highly inbred strains of animals has established that several genetic states predispose to spontaneous carcinogenesis and that incidence increases with advancing age. Resulting malignancies are also characterized by alterations in control of cellular functions indicating that mechanisms controlling specific gene modulation have been altered. Cumulative evidence indicates that non-histone chromosomal proteins (NHCP) control specific gene transcription, alterations in which are reflected as cytosolic protein changes. The objective of this work is to identify relationships between known genetic constitution, differential gene expression, and incidence of primary hepatocellular carcinomas (PHC) that occur in aging populations of recombinant inbred (RI) mice. Also, correlations will be sought between genetic constitution and differential gene expression. Mice used in this study consist of a series of 8 RI strains derived from the progenitor strains C3H/HeN (male) and C57BL/6N (female) and their F1 hybrid B6C3. These highly inbred progenitor strains vary drastically in spontaneous incidenceof PHC, genetic constitution, NHCP, and life span and exhibit differential gene expression. While genetic factors and aging influence tumor incidence in C3H progenitor and F1 hybrid mice, genetic analysis was limited since tumor incidence, a population parameter, cannot be evaluated in individual mice from segregating F2 and back-cross generations. Construction of recombinant inbred (RI) strains now allows a genetic approach to spontaneous tumorigenesis. Young, adult, and aging genetically homozygous RI strains will be monitored for incidence of PHC and characterized for 30 gene markers by starch, acrylamide, and cellulose acetate electrophoretic methods and for distribution of hepatocyte and tumoral non-histone chromosomal and cytoplasmic proteins by high-resolution, two-dimensional polyacrylamide electrophoresis. Genetic composition and specific changes in non-histone chromosomal and cytosolic proteins will be correlated with changes normally occurring in aging populations. The control of incidence of spontaneous hepatocarcinogenesis by a small number of genes (1 to 3) or its polygenic inductive nature will be tested. (S)